Elsevier

Behavioural Brain Research

Volume 204, Issue 2, 7 December 2009, Pages 335-351
Behavioural Brain Research

Review
Modeling cholinergic aspects of schizophrenia: Focus on the antimuscarinic syndrome

https://doi.org/10.1016/j.bbr.2009.04.006Get rights and content

Abstract

Symptoms of schizophrenia, commonly divided into positive symptoms, negative symptoms, and cognitive impairments, exhibit different sensitivity to pharmacological treatments. As such, they are typically modeled in animals by behavioral effects of drugs that evoke these symptoms in humans, such as amphetamine or phencyclidine (PCP). Despite the fact that muscarinic antagonists also evoke a schizophrenia-like syndrome (“antimuscarinic syndrome”) and findings of cholinergic-related alterations in brains of schizophrenia patients, modeling schizophrenia using muscarinic manipulations has been infrequently considered, and the effects of muscarinic blockade on behavioral tasks relevant to schizophrenia have not been adequately characterized. The present review surveys recent attempts to model schizophrenia-related symptoms using manipulations causing cholinergic dysfunction, particularly muscarinic blockade, in well validated behavioral models of schizophrenia, such as prepulse inhibition and latent inhibition.

Introduction

Symptoms of schizophrenia are divided into positive symptoms, negative symptoms, and cognitive impairments, a classification which has replaced the notion that cognitive impairments are associated uniquely with negative symptoms [22], [32], [211]. Treatment of schizophrenia was revolutionized many years ago by the discovery that dopaminergic blockers ameliorate the positive symptoms of the disorder. Yet, for decades now, the challenge facing the pharmacotherapy of schizophrenia has been the development of drugs that target negative and, more critically, cognitive symptoms [101], [120].

Dysfunctions of the central cholinergic system or degeneration of cholinergic cells are involved in the cognitive symptoms that characterize a wide range of neurological disorders (e.g., Alzheimer's disease, Parkinson's disease [4], [5], [30], [304]). These cognitive deficits, including impairments in memory, thinking and language usage, are also observed in schizophrenia patients [127], [239], [276] and therefore also may be associated with cholinergic dysfunction in schizophrenia [94], [267], [303]. Indeed, several lines of evidence suggest an involvement of a cholinergic dysfunction in the pathology of cognitive impairments in schizophrenia, as well as in positive symptoms (for reviews, see refs. [43], [68], [92], [133], [208], [219], [240], [315]). Cholinergic involvement in schizophrenia is further supported by the fact that muscarinic antagonists can evoke a psychotic state (“antimuscarinic psychosis/syndrome”), which includes a range of cognitive and psychotic symptoms resembling schizophrenia (see ref. [315], also see below). However, in contrast to the psychosis-inducing drugs from dopamine agonists (DA) (e.g., amphetamine) and N-methyl-d-aspartate (NMDA) antagonists (e.g., PCP), whose behavioral effects in animals have been widely used to model schizophrenia [137], [247], [259], a similar use of muscarinic antagonists has been limited. Given the increasing acknowledgment of cholinergic dysfunction in schizophrenia and the potential benefits of pro-cholinergic drugs for treatment of persistent cognitive impairments in this disorder, this review surveys the use of manipulations causing cholinergic dysfunction in animals, particularly muscarinic blockade, to model schizophrenia.

Section snippets

Acetylcholine in the central nervous system – a brief overview

Acetylcholine (ACh) was the first neurotransmitter to be discovered, primarily due to its peripheral function in the somatic and autonomic nervous systems. However, the delineation and characterization of the central cholinergic system are still ongoing, particularly in primate and human brain.

Involvement of cholinergic dysfunction in the pathophysiology of schizophrenia

As noted in Section 1, recent years have witnessed a growing focus on cognitive impairments in schizophrenia, leading to increased efforts to identify treatments that target such impairments. Several lines of evidence have converged to promote the interest in the involvement of the cholinergic system in the pathology of cognitive impairments in schizophrenia and in their treatment (see refs. [43], [68], [92], [133], [208], [219], [240], [315]).

Modeling schizophrenia using muscarinic blockade: a potential model of positive and cognitive symptoms in schizophrenia

In spite of the evidence described above for cholinergic involvement in the pathophysiology of schizophrenia, relatively little efforts have been directed to develop and validate cholinergic-based animal models of this disorder. Several reasons converged to sweep aside “cholinergic modeling” of schizophrenia. Thus, while it is well established that nicotine acts to increase DA release in the nucleus accumbens (NAC) similarly to pro-psychotic drugs such as amphetamine (for reviews, see refs. [9]

Summary and conclusions

In recent years, the search for drugs that would treat cognitive impairments in schizophrenia has become one of the major challenges in the field [101], [120]. In this endeavor, valid animal models of schizophrenia play a crucial role. Indeed, preclinical assessment tools for the cognition enhancing capacity of novel drugs have been developed and established [101; MATRICS project – http://www.matrics.ucla.edu]. Given the well-documented involvement of the cholinergic system in cognition, it has

Conflict of interest

None.

Acknowledgments

The research by the author described in this review was supported by the Israel Science Foundation (ISF; grant no. 1234/07) and by the Josef Sagol Fellowship Program in Brain Studies at Tel Aviv University.

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